Preparation of 2-acylamino-1, 3, 4-thiadiazole-5-sulfides



2,805,226 Patented Sept. 3, 1957 PREPARATION OF2-ACYLAMINO-1,3,4-THIADI- AZOLE-S-SULFIDES Richard W. Young, Riverside,and Kathryn H. Wood, Greenwich, Conn., assignors to American CyanamidCompany, New York, N. Y., a corporation of Maine No Drawing. ApplicationJanuary 23, 1956, Serial No. 560,851

g 4 Claims. (Cl. 260-3068) This invention relates to a novel process ofpreparing 2-acylamino-1,3,4-thiadiazole-5-sulfides of the formula:

wherein R is a lower alkyl radical or a monocyclic aralkyl radical.Suitable lower alkyl substituents are methyl, ethyl, propyl, isopropyl,butyl, pentyl, amyl, hexyl, etc. and suitable aralkyl substituents arebenzyl, phene'thyl, phenylpropyl, phenylbutyl, etc.

The compounds produced by the novel process described herein are usefulas intermediates in the preparation of hetrocyclic sulfonamidesdescribed in the Clapp and Roblin U. S. Patent 2,554,816. Theheterocyclic compounds of Clapp et al, are highly useful diuretic agentsbecause of their ability to inhibit the enzyme carbonicanhydrase. Assuch, the compounds of Clapp et al. are highly useful for the treatmentof edema due to congestive heart failure. These compounds have also beenfound useful in the treatment of epilepsy and glaucoma. The usefulnessof the compounds of Clapp et al. has been adequately described in themedical literature.

The preparation of the compounds described herein may be accomplished byreacting a suitable acyl isothiocyanate, such as acetylisothiocyanate,with a dithiocarbazate, such as benzyldithiocarbazate, in the presenceof a suitable non-hydroxylated organic solvent, such as toluene, attemperatures ranging from room temperature .to about 200 C.

The acyl isothiocyanate used in this reaction may be any suitable acylisothiocyanate, such as acetylisothiocyanate, phopionylisothiocyanate,butyrylisothiocyanate,

' isobutyrylisothiocyanate, n-valerylisothiocyanate, etc.

Suitable inert organic solvents useful in this reaction aredimethylformamide, chloroform, carbon tetrachloride, dioxane, benzene,chlorobenzene, xylenes, etc.

The process of this invention may be illustrated schematically belowusing acetylisothiocyanate as an example of a suitable acylisothiocyanate and benzyldithiocarbazate as an example of adithiocarbazate.

I I Has CHa-E-NH S SCHm The acylaminothiadiazole sulfides of thisinvention may be converted to the sulfonamides described by Clapp andRoblin by forming the corresponding sulfonylchloride derivative and thenamidating with liquid ammonia or ammonium hydroxide as described in thecopending application of Richard W. Young, Serial No. 406,605, filedJanuary 27, 1954.

The invention will be described in greater detail in conjuction with thefollowing specific examples in which the parts are by weight unlessotherwise specified.

Example 1 A solution of 3.97 parts of benzyldithiocarbazate and 2.02parts of acetylisothiocyanate in 20 parts by volume of toluene is heldat reflux temperature (ca. for 3 hours, after which time most of thehydrogen sulfide has evolved. The solution is cooled and concentrated inan air stream overnight. The resultant solid is slurried with ether andfiltered off, giving 4.2 parts of 2-acetylamino 5 benzylmercapto 1,3,4thiadiazole, M. P. 163-168".

Example 2 The procedure of Example 1 is followed with the exception thattetrahydrofuran is used as the solvent and the refluxing is continuedfor 6 hours. The same product is obtained.

Example 3 The procedure of Example 1 is followed with the exception that20 parts by volume of ethyl alcohol is used as the solvent. The sameproduct is obtained.

Example 4 The procedure of Example 1 is followed except that no solventis used and the mixture is heated on the steam bath for 30 minutes. Thesame product is obtained.

ExampleS The procedure of the preceding examples is followed except thatan equivalent quantity of propionylisothiocyanate is used.2-propionylamino-5-benzylmercapto-1, 3,4-thiadiazole is produced.

Example 6 The procedure of the preceding examples is followed exceptthat an equivalent quantity of butyrylisothiocyanate is used.2-butyrylamino-S-benzylmercapto-1,3,4- thiadiazole is produced.

We claim:

1. The process of preparing compounds having the general formula:

R-E-NlllgJ-SCHM 4. The process according to claim 3 in which the solventis toluene.

References Cited in the file of this patent Bambas: HeterocyclicCompounds, pp. 143-158 (1952), Interscience Publishers, Inc., New York.

1. THE PROCESS OF PREPARING COMPOUNDS HAVING THE GENERAL FORMULA: